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McTeague is a dentist of limited intellect from a poor miner's family, who has opened a dentist shop on Polk Street in San Francisco. (His first name is never revealed; other characters in the novel call him simply "Mac.") His best friend, Marcus Schouler, brings his cousin, Trina Sieppe, whom he is courting, to McTeague's parlor for dental work. McTeague becomes infatuated with her while working on her teeth, and Marcus graciously steps aside. McTeague successfully woos Trina. Shortly after McTeague and Trina have kissed and declared their love for each other, Trina discovers that she has won $5,000 from a lottery ticket. In the ensuing celebration Trina's mother, Mrs. Sieppe, announces that McTeague and Trina are to marry. Marcus becomes jealous of McTeague, and claims that he has been cheated out of money that would have been rightfully his if he had married Trina.

The marriage takes place, and Mrs. Sieppe, along with the rest of Trina's family, move away from San Francisco, leaving her alone with McTeague. Trina proves to be a parsimonious wife; she refuses to touch the principal of her $5,000, which she invests with her uncle. She insists that she and McTeague must live on the earnings from McTeague's dental practice, the small income from the $5,000 investment, and the bit of money she earns from carving small wooden figures of Noah's animals and his Ark for sale in her uncle's shop. Secretly, she accumulates penny-pinched savings in a locked trunk. Though the couple are happy, the friendship between Marcus and Mac deteriorates. More than once the two men come to grips; each time McTeague's immense physical strength prevails, and eventually he breaks Marcus's arm in a fight. When Marcus recovers, he goes south, intending to become a rancher; before he leaves, he visits the McTeagues, and he and Mac part apparently as friends.

Catastrophe strikes when McTeague is debarred from practicing dentistry by the authorities; it becomes clear that before leaving, Marcus has taken revenge on Mac by informing city hall that he has no license or degree. McTeague loses his practice and the couple are forced to move into successively poorer quarters as Trina becomes more and more miserly. Their life together deteriorates until McTeague takes all Trina's domestic savings (amounting to $400 or roughly $10,000 in 2010 values) and abandons her. Meanwhile, Trina falls completely under the spell of money and withdraws the principal of her prior winnings in gold from her uncle's firm so she can admire and handle the coins in her room, at one point spreading them over her bed and rolling around in them.

When McTeague returns, destitute once more, she refuses to give him money even for food. Aggravated and made violent by whiskey, McTeague beats her to death. He takes the entire hoard of gold and heads out to a mining community that he had left years before. Sensing pursuit, he makes his way south towards Mexico; meanwhile, Marcus hears of the murder and joins the hunt for McTeague, finally catching him in Death Valley. In the middle of the desert Marcus and McTeague fight over McTeague's remaining water and, when that is lost and they are already doomed, over Trina's $5,000. McTeague kills Marcus, but as he dies, Marcus handcuffs himself to McTeague. The final, dramatic image of the novel is one of McTeague stranded, alone and helpless. He is left with only the company of Marcus's corpse, to whom he is handcuffed, in the desolate, arid waste of Death Valley.

Greed, Erich von Stroheim's film version of McTeague, was made in 1924. In its original form it lasted approximately eight hours but was drastically cut by the studio, MGM, and most of the excised footage has been lost.

An earlier adaptation was titled McTeague (1916). No copies of that film are known to exist.

Karen Kearns produced a radio drama version of McTeague in 1989, under a Corporation for Public Broadcasting Fellowship. The program featured Stacy Keach, Carol Kane, Hector Elizondo, JoBeth Williams, Michael York, Katherine Helman, Ed Asner, Joe Spano, and many other well-known television and film actors.